Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes
Objective. Iguratimod, a novel disease-modifying anti-rheumatic drug for the treatment of rheumatoid arthritis, has been approved in China and Japan. Here, we aimed to find whether iguratimod can inhibit the aggressive behavior and promote apoptosis of rheumatoid fibroblast-like synoviocytes (RA-FLS...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2019/6929286 |
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| author | Jin Lin Ye Yu Xuanwei Wang Yini Ke Chuanyin Sun Lihuan Yue Guanhua Xu Bei Xu Liqin Xu Heng Cao Danyi Xu Nancy Olsen Weiqian Chen |
| author_facet | Jin Lin Ye Yu Xuanwei Wang Yini Ke Chuanyin Sun Lihuan Yue Guanhua Xu Bei Xu Liqin Xu Heng Cao Danyi Xu Nancy Olsen Weiqian Chen |
| author_sort | Jin Lin |
| collection | DOAJ |
| description | Objective. Iguratimod, a novel disease-modifying anti-rheumatic drug for the treatment of rheumatoid arthritis, has been approved in China and Japan. Here, we aimed to find whether iguratimod can inhibit the aggressive behavior and promote apoptosis of rheumatoid fibroblast-like synoviocytes (RA-FLSs). Methods. The proliferation of RA-FLSs was assessed by 5-ethynyl-2′-deoxyuridine test and Cell Counting Kit-8. Migration and invasion were determined by the wound test and a transwell assay. Apoptosis was tested by flow cytometry. The mRNA expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines in RA-FLSs were measured by quantitative PCR and ELISA. To gain insight into the molecular signaling mechanisms, we determined the effect of iguratimod on the activation of mitogen-activated protein kinases (MAPK) signaling pathways by the cellular thermal shift assay (CETSA) and western blot. Results. Iguratimod treatment significantly reduced the proliferation, migration, and invasive capacities of RA-FLSs in a dose-dependent manner in vitro. MMP-1, MMP-3, MMP-9, Interleukin-6 (IL-6), and monocyte chemoattractant protein-1 mRNA and protein levels were all decreased after treatment with iguratimod. Furthermore, tumor necrosis factor-alpha- (TNF-α-) induced expression of phosphorylated c-Jun N-terminal kinases (JNK) and P38 MAPK were inhibited by iguratimod. Additionally, iguratimod promoted the apoptosis of RA-FLSs. Most importantly, iguratimod was shown to directly interact with JNK and P38 protein by CETSA assay. Moreover, activating transcription factor 2 (ATF-2), a substrate of both JNK and P38, was suppressed by iguratimod. Conclusions. Our findings suggested that the therapeutic effects of iguratimod on RA might be, in part, due to targeting the aggressive behavior and apoptosis of RA-FLSs. |
| format | Article |
| id | doaj-art-434eafbb92664a1e85d66bb7c10895f1 |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-434eafbb92664a1e85d66bb7c10895f12025-02-03T01:30:05ZengWileyJournal of Immunology Research2314-88612314-71562019-01-01201910.1155/2019/69292866929286Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like SynoviocytesJin Lin0Ye Yu1Xuanwei Wang2Yini Ke3Chuanyin Sun4Lihuan Yue5Guanhua Xu6Bei Xu7Liqin Xu8Heng Cao9Danyi Xu10Nancy Olsen11Weiqian Chen12Department of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Orthopedics, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaDivision of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey 17033, USADepartment of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, ChinaObjective. Iguratimod, a novel disease-modifying anti-rheumatic drug for the treatment of rheumatoid arthritis, has been approved in China and Japan. Here, we aimed to find whether iguratimod can inhibit the aggressive behavior and promote apoptosis of rheumatoid fibroblast-like synoviocytes (RA-FLSs). Methods. The proliferation of RA-FLSs was assessed by 5-ethynyl-2′-deoxyuridine test and Cell Counting Kit-8. Migration and invasion were determined by the wound test and a transwell assay. Apoptosis was tested by flow cytometry. The mRNA expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines in RA-FLSs were measured by quantitative PCR and ELISA. To gain insight into the molecular signaling mechanisms, we determined the effect of iguratimod on the activation of mitogen-activated protein kinases (MAPK) signaling pathways by the cellular thermal shift assay (CETSA) and western blot. Results. Iguratimod treatment significantly reduced the proliferation, migration, and invasive capacities of RA-FLSs in a dose-dependent manner in vitro. MMP-1, MMP-3, MMP-9, Interleukin-6 (IL-6), and monocyte chemoattractant protein-1 mRNA and protein levels were all decreased after treatment with iguratimod. Furthermore, tumor necrosis factor-alpha- (TNF-α-) induced expression of phosphorylated c-Jun N-terminal kinases (JNK) and P38 MAPK were inhibited by iguratimod. Additionally, iguratimod promoted the apoptosis of RA-FLSs. Most importantly, iguratimod was shown to directly interact with JNK and P38 protein by CETSA assay. Moreover, activating transcription factor 2 (ATF-2), a substrate of both JNK and P38, was suppressed by iguratimod. Conclusions. Our findings suggested that the therapeutic effects of iguratimod on RA might be, in part, due to targeting the aggressive behavior and apoptosis of RA-FLSs.http://dx.doi.org/10.1155/2019/6929286 |
| spellingShingle | Jin Lin Ye Yu Xuanwei Wang Yini Ke Chuanyin Sun Lihuan Yue Guanhua Xu Bei Xu Liqin Xu Heng Cao Danyi Xu Nancy Olsen Weiqian Chen Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes Journal of Immunology Research |
| title | Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes |
| title_full | Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes |
| title_fullStr | Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes |
| title_full_unstemmed | Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes |
| title_short | Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes |
| title_sort | iguratimod inhibits the aggressiveness of rheumatoid fibroblast like synoviocytes |
| url | http://dx.doi.org/10.1155/2019/6929286 |
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